STEREOLOGY AND RHEOLOGY OF INTIMA DAMAGE AT BIFURICATION

对于特定的血流动力学应力，需要测试的假设是：(i)

For specific hemodynamic stresses, the hypotheses to be tested are that (i) damage is more profound at cerebral artery bifurcations than in adjacent branches or at extracranial bifurcations and (ii) such damage is initiated from the intima. The architecture of cerebral artery bifurcations will be examined in rabbits with aortic coarctation hypertension, atherosclerosis, or carotid ligation and from human autopsies. The focus will be on young adult male rabbits with appropriate controls. Quantitative stereological methods will be employed in order to comment on the role of endothelium, smooth muscle (SM) and the internal elastic lamina (IEL) in possible mechanical weakness of the arterial wall leading to atherosclerosis and aneurysm formation. The specific aims related to the structure of arterial bifurcations and medial gaps are (a) determine the patterns and precise orientation of endothelial and SM cells (b) map out the distribution, location and sizes of fenestrations in the IEL (c) quantitate any differences in proportional composition of the bifurcation wall compared to non-branching segments (d) determine the arrangement and interrelationship among cellular and acellular components of the intima. These structural parameters will be compared depending on (I) location (II) pressure or flow and (III) the existence of related pathology (atherosclerosis or aneurysms). The human cerebral circulation has a very high incidence of medial defects, minute aneurysms, and saccular aneurysms which may rupture resulting in subarachnoid hemorrhage, and arterial spasm. It is felt that a combination of congenital and/or acquired factors might give rise to aneurysm formation and rupture but there is as yet no accepted etiology. Stehbens (1) states "further information pertaining to the degenerative changes and hemodynamic stresses at arterial forks is the prerequisite for a more detailed outline of the pathogenesis of cerebral aneurysms". Only a quantitative stereological approach with mechanical analysis can provide this information. Revelance of experimental studies will be enhanced since the pattern of the rabbit and human cerebral vessels is very similar. Considering the incidence, mortality and morbidity of subarachnoid hemorrhage, it is important to answer fundamental questions about initial changes in bifurcation architecture which could be precursors for the pathogenesis of cerebral aneurysms which could lead to reevaluation of risk factors. More than half of Americans die from cardiovascular diseases of which most are related to the atherosclerotic process and this process is primarily due to familial hypercholesterolemia in less than 5% of cases (2). Cholesterol fed rabbits will provide data on the deposition of fat at carotid, cerebral and ear bifurcations. Yet altered blood pressure and flow may provide insights into the multifactorial and synergistic alterations which cause intimal cushions to form at the lateral angles and other sites about bifurcations. The same factors which cause abnormal permeability in small cerebral vessels may be a factor in intimal changes of larger bifurcations. Furthermore, since calcium entry blockers may have a protective effect against endothelial and SM damage, clinical doses of these drugs will be used to evaluate if they help prevent observed lesions or enhance their regression.